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Year : 2021  |  Volume : 24  |  Issue : 2  |  Page : 173-177

Biotin-thiamine-responsive basal ganglia disease in children: A treatable neurometabolic disorder

1 Pediatric Neurology, Department of Pediatrics, Advanced Pediatric Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Associated Kalawati Saran Children's Hospital, New Delhi, India

Date of Submission01-Sep-2020
Date of Acceptance28-Sep-2020
Date of Web Publication31-Mar-2021

Correspondence Address:
Dr. Suvasini Sharma
Associate Professor, Neurology Division, Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi - 110 001
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aian.AIAN_952_20

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Biotin-thiamine-responsive basal ganglia disease is a rare, autosomal recessive, treatable, neurometabolic disorder associated with biallelic pathogenic variations in the SLC19A3 gene. The condition may present as an early-childhood encephalopathy, an early-infantile lethal encephalopathy with lactic acidosis, with or without infantile spasms, or a late-onset Wernicke-like encephalopathy. The key radiological features are bilateral, symmetrical lesions in the caudate, putamen, and medial thalamus, with variable extension into the brain stem, cerebral cortex, and cerebellum. Treatment is life long and includes initiation of high dose biotin and thiamine. Genetic testing confirms the diagnosis. The prognosis depends on the time from diagnosis to the time of vitamin supplementation. The genotype-phenotype correlations are not clear yet, but the early infantile phenotype portends a poorer prognosis. We provide a brief overview of the disorder and emphasize the initiation of high-dose biotin and thiamine in infants and children with unexplained encephalopathy and basal ganglia involvement.

Keywords: Basal ganglia, biotin, encephalopathy, IEM, metabolic, SLC19A3, thiamine

How to cite this article:
Saini AG, Sharma S. Biotin-thiamine-responsive basal ganglia disease in children: A treatable neurometabolic disorder. Ann Indian Acad Neurol 2021;24:173-7

How to cite this URL:
Saini AG, Sharma S. Biotin-thiamine-responsive basal ganglia disease in children: A treatable neurometabolic disorder. Ann Indian Acad Neurol [serial online] 2021 [cited 2021 Oct 20];24:173-7. Available from:

   Introduction Top

Biotin-thiamine-responsive basal ganglia disease (BTBGD) is a rare, autosomal recessive, treatable, neurometabolic disorder associated with biallelic pathogenic variations in the solute carrier family 19 member 3 (SLC19A3) gene.[1] Ozand et al. first described the entity in 1998 as a childhood encephalopathy responsive to biotin and named 'biotin-responsive basal ganglia disease'.[2] Since then, the disorder has come a long way with expansion of phenotypic subtypes and age at presentation, the discovery of underlying genetic variations, pan-ethnic distribution, and therapeutic response to high-dose biotin and thiamine. The terminology has subsequently been changed to include biotin and thiamine responsiveness to denote this group of disorders.[3] Overall, a birth prevalence of 1 in 215000, and a carrier frequency of 1 in 232 persons in the general population have been estimated for all BTBGD phenotypes.[4] Based on the genetic screening of healthy newborn babies, a carrier frequency of 1 in 500 individuals and a prevalence of one in millions has been estimated in the Saudi population.[5] The disorder is probably underdiagnosed and may be missed as Leigh syndrome, mitochondrial disease, or infection-associated demyelination syndromes. When untreated or inadequately treated, the condition presents with progressive neurodegeneration and death. In this review, we provide a brief overview of the BTBGD associated with SLC19A3 variations to sensitize the readers to this eminently treatable neurometabolic disorder. We also emphasize the initiation of high-dose biotin and thiamine in infants and children with encephalopathy and basal ganglia involvement.

   Pathophysiology of Thiamine-based Neurological Disorders Top

Thiamine, commonly known as vitamin B1 or aneurine, is a water-soluble, essential vitamin for humans. Thiamine pyrophosphate (TPP) is the most metabolically active form of thiamine in the body.[1] [Table 1] provides a list of enzymes where thiamine is a cofactor and the disorders associated with thiamine metabolism.[6],[7] The human SLC19A3 gene has been mapped to chromosome 2q36.3 in 2005.[8] It encodes a second human thiamine transporter.[9] In SLC19A3-associated disorders, the mutated transporter is either incorrectly localized in the cells or has a reduced affinity for thiamine, or fails to up-regulate the gene expression during periods of metabolic stress, thus restricting the transport of thiamine into the cells.[10] When given in high doses, the increased concentration of thiamine in the blood probably overcomes the receptor block.[11] As biotin is not a substrate for the thiamine transporter, the role of biotin supplementation is not clear.[12] One hypothesis suggests that the high dose biotin allows the accumulating pyruvate in thiamine deficiency to bypass the Kreb's cycle using the biotin-dependent pyruvate carboxylase enzyme.[13] This leads to the formation of oxaloacetate, which then enters the Krebs cycle instead of the acetyl-CoA and overcomes the metabolic block. The stress-induced upregulation of SLC19A3 expression is an adaptive response and is lost in patients with BTBGD.[10]
Table 1: The enzymes and common disorders associated with thiamine in humans[1]

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   Clinical Features Top

Ozand et al. initially described the disorder in 1998 as early-onset (before four years of age), subacute encephalopathy, commonly triggered by a febrile illness or stress, seizures, external ophthalmoplegia, generalized secondary dystonia, quadriparesis, coma, and even death.[2] Over the years, several phenotypes have been associated with SLC19A3-related basal ganglia disease and thiamine responsiveness. Broadly, these can be divided into three forms based on their age of presentation:

  • Early childhood encephalopathy: This is the classical form originally associated with pathogenic variations in SLC19A3. The disease typically presents in early or late childhood between 3 and 10 years of age with episodic encephalopathy, neuroregression, recurrent seizures (even status epilepticus), spasticity, severe extrapyramidal involvement (even status dystonicus), gait abnormalities, behavioral problems, and bilateral affection of the corpus striatum and cerebral cortex, with or without brain stem involvement.[3] The encephalopathy is often triggered by fever, metabolic stress, trauma, vaccination, or extensive exercise.[1],[14] Seizures are often seen associated with the acute state but may also be the presenting symptom. Myoclonic jerks, infantile spasms, focal or generalized-onset motor seizures, generalized or focal status epilepticus, or a combination of several seizure types may be seen.
  • Early infantile form: A more severe presentation has been described in early infancy that presents acutely as a rapidly progressing encephalopathy, seizures, lactic acidosis, neuroregression, poor response to thiamine, and premature death (often described as early-infantile lethal encephalopathy).[15],[16] Some infants present with typical infantile spasms, severe psychomotor retardation, and progressive brain atrophy.[17] The latter condition is often described as a distinct phenotype under BTBGD. Sometimes, these patients present with infantile spasms in follow-up after an acute crisis. Epilepsy may evolve into Lennox-Gastaut syndrome with multiple seizure types.[18] The common feature in all these presentations is the bilateral basal ganglia lesions and an infantile-onset of severe neurological symptoms (as early as in the newborn period).[18]
  • Late-onset Wernicke-like encephalopathy: often presents in the second decade with acute-onset neurological symptoms such as epilepsy, nystagmus, ophthalmoplegia, and ataxia. This presentation has been associated with compound heterozygous variations in the SLC19A3 and shows a reversal of symptoms with high-dose thiamine supplementation.[19]

   Investigations Top


BTBGD is not associated with a specific biochemical metabolite, which may clinch the diagnosis. As the underlying biochemical alteration is the failure of cellular energy mechanisms, it is often reflected as lactic acidosis in the blood and urine. The excretion of organic acids in the urine in BTBGD is variable. It may reflect high concentrations of isobutyric, 2-hydroxy-isovaleric, 2,4-di-hydroxybutyric, 3-hydroxybutyric, α-keto glutaric, 2-hydroxyglutaric, glutaric, succinic, 2-ketoadipic and 4-hydroxy-phenyl lactic acids.[1],[14] Plasma elevations of alanine, leucine, and isoleucine have also been reported.[11],[16] Muscle histology and electron transport chain complex activities are normal.

Thiamine assays

A normal concentration of total thiamine in the blood, and a low level of free thiamine in the cerebrospinal fluid and fibroblasts is seen.[11],[20] Although not routinely available, the demonstration of decreased free thiamine in the cerebrospinal fluid has been suggested as a biomarker for diagnosis and monitoring of treatment.[1]

Magnetic resonance imaging (MRI)

The key radiological feature is the presence of bilateral, symmetrical lesions in the caudate nuclei, putamen, and medial thalamus, with variable extension into the brain stem, cerebral cortex, and cerebellum [Figure 1]a, [Figure 1]b.[1] The swelling of the nuclei in the acute stage is due to cytotoxic edema and is reflected as diffusion restriction. Mixed diffusion abnormalities in the lesions may represent a combination of cytotoxic edema, vasogenic edema, and encephalomalacia.[4] The lesions may progress and lead to necrosis in the caudate and putamen. The involvement of globus pallidi and brainstem has been associated with a poor prognosis.[14] The cortical lesions typically involve the depth of the sulci.[15] There is an absence of significant contrast enhancement.[21] The early infantile form shows more extensive involvement. It has been categorized into an acute, post-acute, intermediate, and end-stage phase by Kevelam et al.[15] The acute swelling partially resolves and leads to rarefaction and cystic degeneration of deep grey nuclei and subcortical white matter. This is followed by progressive atrophy of the previously mentioned structures and cortical thinning in the intermediate and end-stage.[15]
Figure 1: (a-b): Magnetic resonance imaging of the brain T2-weighted axial sections showing hyperintensities in bilateral caudate, putamen, cortical and subcortical white matter, with gliosis in the right putamen and left temporal lobe (B) bilateral involvement of the cerebellar hemispheres

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Sparing of mammillary bodies and more extensive cortical involvement is seen in BTBGD compared to Wernicke's encephalopathy (acquired thiamine deficiency).[22],[23] MR spectroscopy is non-specific. It often shows an increased lactate peak in the basal ganglia indicating energy failure and anaerobic metabolism during an acute crisis. Additionally, moderately decreased NAA to creatine ratio may be seen over the basal ganglia suggestive of neuronal loss. A pyruvate peak has been noted in the parietal white matter in patients with BTBGD akin to pyruvate dehydrogenase/succinate dehydrogenase deficiency. It reflects the role of thiamine as a cofactor for the mitochondrial enzyme pyruvate dehydrogenase.[4]


There are no pathognomonic patterns associated with BTBGD. The early infantile presentation has been reported to be associated with diffuse slowing, asymmetrical sleep spindles, generalized burst suppression, hypsarrhythmia, polyspike-wave complexes, and multifocal discharges.[18]

Next-generation sequencing

Demonstration of biallelic pathogenic variations in the SLC19A3 gene confirms the diagnosis and offers the chance for prenatal counseling. Loss-of-function mutations have been associated with defective transporter function. The majority of the described variations are missense, truncating (nonsense or frameshift), and rarely large deletions affecting the promoter region.[24] The genotype-phenotype and genotype-receptor function correlations are poor. Siblings from the same family may have different outcomes. A founder mutation in exon 5 (c. 1264 A > G [p.T422A]) has been described from Saudi Arabia.[3] As the disorder is pan-ethnic now, the ancestry is expanding, and more knowledge about the genetic footprint of the condition is expected in the future.

   Differential Diagnosis Top

Based on the above mentioned clinical, biochemical and radiological features, diagnostic criteria for SLC19A3-associated BTBGD have been suggested [Table 2].[1],[14] We recommend that any combination of these features be used for suspecting SLC19A3-associated thiamine dysfunction syndrome. The acute encephalopathy due to thiamine metabolic dysfunction needs to be differentiated from infectious inflammatory central nervous system disorders (including demyelination, autoimmune, and vasculitis), toxic encephalopathies, and Wernicke encephalopathy. The inherited disorders that need to be excluded include organic acidemia, maple syrup urine disease, mitochondrial disorders, Wilson disease, Huntington disease, neurotransmitter disorders, and inherited dystonia.[22]
Table 2: Key features associated with BTBGD in children

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   Management Top

Timely recognition and management of the 'treatable' metabolic disorders improve the neurological outcomes, and the quality of life of the patients.[25] BTBGD is a potentially treatable neurometabolic disorder. Supportive care during an acute crisis of BTBGD includes intensive care support, maintenance of ventilation, treatment of seizures, empiric antibiotics until infectious trigger ruled out, and anti-dystonia measures. Fever down-regulates SLC19A3 and may worsen the clinical condition; hence, temperature control should be aggressive.

Specific measures include the initiation of thiamine and biotin supplementation. The doses are higher than usually required for biotinidase deficiency and mitochondrial disorders. Biotin is initiated at 5-10 mg/kg/d, and thiamine at 10-40 mg/kg/d (300-900 mg).[22],[26] Administration of high-dose thiamine restores its level in the cells and the cerebrospinal fluid, reduces the lactic acidosis, and limits cerebral edema and necrosis. Abrupt withdrawal of thiamine therapy has been associated with the recurrence of metabolic crises within 30 days.[19] During an acute crisis, the dose may be doubled and given intravenously. Intravenous dosing may be associated with transient local irritation or pruritus. Treatment is life-long. Certain drugs such as metformin, famotidine, chloroquine, and verapamil inhibit the thiamine transporter and should be avoided in these patients.[27] Stress and trauma can precipitate an acute crisis. Routine immunization is recommended.

   Outcome Top

The prognosis in BTBGD depends mainly on the timely diagnosis and initiation of vitamin supplementation.[28] Additional factors affecting the outcomes include the age of onset and the underlying genetic variation. The early childhood phenotype of BTBGD often shows clinical improvement and even remission with biotin and thiamine supplementation. However, the efficacy of these vitamins in early infantile forms is not established. Progressive brain atrophy and persisting infantile spasms often result in death by two years of age. The missense variations are associated with good response to biotin and thiamine, probably due to the residual activity of the defective receptor. On the other hand, frameshift variations or deletions may altogether abolish the transporter and cause an insufficient therapeutic response.[10],[28] In a recent study on nine patients with BTBGD, nearly half of the patients had an average cognition (56%), mild-severe delay (44%) and poor visual-motor integration (55%).[28] Understanding and mathematical problem solving were the least affected domains.[28] Long-term data on the surviving patients is limited and shall evolve with more recognition and survival.

   Conclusion Top

BTBGD is a pan-ethnic, underdiagnosed, treatable neurometabolic disorder. It should be suspected in all infants and children with unexplained encephalopathy and bilateral basal ganglia lesions on neuroimaging, with or without lactic acidosis. High dose biotin and thiamine should be administered to all these patients during the emergency care itself to optimize the outcomes and to identify the misdiagnosed cases. Genetic testing confirms the diagnosis and treatment is life-long. The prognosis depends on the time from diagnosis to the time of vitamin supplementation. The genotype-phenotype correlations are not clear yet, but the early infantile phenotype portends a poorer prognosis.



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   References Top

Marce-Grau A, Marti-Sanchez L, Baide-Mairena H, Ortigoza-Escobar JD, Perez-Duenas B. Genetic defects of thiamine transport and metabolism: A review of clinical phenotypes, genetics, and functional studies. J Inherit Metab Dis 2019;42:581-97.  Back to cited text no. 1
Ozand PT, Gascon GG, Al Essa M, Joshi S, Al Jishi E, Bakheet S, et al. Biotin-responsive basal ganglia disease: A novel entity. Brain 1998;121:1267-79.  Back to cited text no. 2
Alfadhel M, Almuntashri M, Jadah RH, Bashiri FA, Al Rifai MT, Al Shalaan H, et al. Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: A retrospective review of the clinical, radiological and molecular findings of 18 new cases. Orphanet J Rare Dis 2013;8:83.  Back to cited text no. 3
Ferreira CR, Whitehead MT, Leon E. Biotin-thiamine responsive basal ganglia disease: Identification of a pyruvate peak on brain spectroscopy, novel mutation in SLC19A3, and calculation of prevalence based on allele frequencies from aggregated next-generation sequencing data. Am J Med Genet A 2017;173:1502-13.  Back to cited text no. 4
Alfadhel M, Umair M, Almuzzaini B, Alsaif S, AlMohaimeed SA, Almashary MA, et al. Targeted SLC19A3 gene sequencing of 3000 Saudi newborn: A pilot study toward newborn screening. Ann Clin Transl Neurol 2019;6:2097-103.  Back to cited text no. 5
Eudy JD, Spiegelstein O, Barber RC, Wlodarczyk BJ, Talbot J, Finnell RH. Identification and characterization of the human and mouse SLC19A3 gene: A novel member of the reduced folate family of micronutrient transporter genes. Mol Genet Metab 2000;71:581-90.  Back to cited text no. 6
Labay V, Raz T, Baron D, Mandel H, Williams H, Barrett T, et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat Genet 1999;22:300-4.  Back to cited text no. 7
Zeng WQ, Al-Yamani E, Acierno JS, Jr., Slaugenhaupt S, Gillis T, MacDonald ME, et al. Biotin-responsive basal ganglia disease maps to 2q36.3 and is due to mutations in SLC19A3. Am J Hum Genet 2005;77:16-26.  Back to cited text no. 8
Rajgopal A, Edmondnson A, Goldman ID, Zhao R. SLC19A3 encodes a second thiamine transporter ThTr2. Biochim Biophys Acta 2001;1537:175-8.  Back to cited text no. 9
Schanzer A, Doring B, Ondrouschek M, Goos S, Garvalov BK, Geyer J, et al. Stress-induced upregulation of SLC19A3 is impaired in biotin-thiamine-responsive basal ganglia disease. Brain Pathol 2014;24:270-9.  Back to cited text no. 10
Ortigoza-Escobar JD, Serrano M, Molero M, Oyarzabal A, Rebollo M, Muchart J, et al. Thiamine transporter-2 deficiency: Outcome and treatment monitoring. Orphanet J Rare Dis 2014;9:92.  Back to cited text no. 11
Subramanian VS, Marchant JS, Said HM. Biotin-responsive basal ganglia disease-linked mutations inhibit thiamine transport via hTHTR2: Biotin is not a substrate for hTHTR2. Am J Physiol Cell Physiol 2006;291:C851-9.  Back to cited text no. 12
Kohrogi K, Imagawa E, Muto Y, Hirai K, Migita M, Mitsubuchi H, et al. Biotin-responsive basal ganglia disease: A case diagnosed by whole exome sequencing. J Hum Genet 2015;60:381-5.  Back to cited text no. 13
Ortigoza-Escobar JD, Alfadhel M, Molero-Luis M, Darin N, Spiegel R, de Coo IF, et al. Thiamine deficiency in childhood with attention to genetic causes: Survival and outcome predictors. Ann Neurol 2017;82:317-30.  Back to cited text no. 14
Kevelam SH, Bugiani M, Salomons GS, Feigenbaum A, Blaser S, Prasad C, et al. Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy. Brain 2013;136:1534-43.  Back to cited text no. 15
Perez-Duenas B, Serrano M, Rebollo M, Muchart J, Gargallo E, Dupuits C, et al. Reversible lactic acidosis in a newborn with thiamine transporter-2 deficiency. Pediatrics 2013;131:e1670-5.  Back to cited text no. 16
Yamada K, Miura K, Hara K, Suzuki M, Nakanishi K, Kumagai T, et al. A wide spectrum of clinical and brain MRI findings in patients with SLC19A3 mutations. BMC Med Genet 2010;11:171.  Back to cited text no. 17
Sremba LJ, Chang RC, Elbalalesy NM, Cambray-Forker EJ, Abdenur JE. Whole exome sequencing reveals compound heterozygous mutations in SLC19A3 causing biotin-thiamine responsive basal ganglia disease. Mol Genet Metab Rep 2014;1:368-72.  Back to cited text no. 18
Kono S, Miyajima H, Yoshida K, Togawa A, Shirakawa K, Suzuki H. Mutations in a thiamine-transporter gene and Wernicke's-like encephalopathy. N Engl J Med 2009;360:1792-4.  Back to cited text no. 19
Ortigoza-Escobar JD, Molero-Luis M, Arias A, Oyarzabal A, Darin N, Serrano M, et al. Free-thiamine is a potential biomarker of thiamine transporter-2 deficiency: A treatable cause of Leigh syndrome. Brain 2016;139:31-8.  Back to cited text no. 20
Alabdulqader MA, Al Hajjaj S. Biotin-thiamine-responsive basal ganglia disease: Case report and follow-up of a patient with poor compliance. Child Neurol Open 2018;5:2329048X18773218.  Back to cited text no. 21
Tabarki B, Al-Shafi S, Al-Shahwan S, Azmat Z, Al-Hashem A, Al-Adwani N, et al. Biotin-responsive basal ganglia disease revisited: Clinical, radiologic, and genetic findings. Neurology 2013;80:261-7.  Back to cited text no. 22
Zuccoli G, Siddiqui N, Bailey A, Bartoletti SC. Neuroimaging findings in pediatric Wernicke encephalopathy: A review. Neuroradiology. 2010;52:523-9.  Back to cited text no. 23
Flones I, Sztromwasser P, Haugarvoll K, Dolle C, Lykouri M, Schwarzlmuller T, et al. Novel SLC19A3 promoter deletion and allelic silencing in biotin-thiamine-responsive basal ganglia encephalopathy. PLoS One 2016;11:e0149055.  Back to cited text no. 24
Saini AG, Sharma S. Movement disorders in inherited metabolic diseases in children. Ann Indian Acad Neurol 2020;23:332-7.  Back to cited text no. 25
  [Full text]  
Alfadhel M, Tabarki B. SLC19A3 gene defects sorting the phenotype and acronyms: Review. Neuropediatrics 2018;49:83-92.  Back to cited text no. 26
Liang X, Chien HC, Yee SW, Giacomini MM, Chen EC, Piao M, et al. Metformin is a substrate and inhibitor of the human thiamine transporter, THTR-2 (SLC19A3). Mol Pharm 2015;12:4301-10.  Back to cited text no. 27
Alfadhel M, Al-Bluwi A. Psychological assessment of patients with biotin-thiamine-responsive basal ganglia disease. Child Neurol Open 2017;4:2329048X17730742.  Back to cited text no. 28


  [Figure 1]

  [Table 1], [Table 2]


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